Basic Science and Pathogenesis

Background: Bridging integrator 1 (BIN1), one of the most strongly associated gene with Alzheimer's disease (AD). It has been reported to play a role in the pathological processes of AD; however, the exact mechanism has not yet been completely found.

Method: Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 495) was the discovery cohort, and the Chinese Alzheimer's Biomarker and LifestylE (CABLE, N = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model was used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of sTREM2 on AD pathology.

Result: In the ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and the levels of CSF phosphorylated-tau (P-tau) (Pc = 0.017; 0.010, respectively) and total-tau (T-tau) (Pc = 0.011; 0.013, respectively). The BIN1 loci were also found to be correlated with the levels of CSF sTREM2 (Pc = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of the BIN1 loci with P-tau (rs7561528: Prop = 20.9% of total effect; rs744373: Prop = 24.9% of total effect) and T-tau (rs7561528: Prop = 36.6% of total effect; rs744373: Prop = 44.1% of total effect). The analysis in CABLE study replicated the mediation role of rs7561528.

Conclusion: This study demonstrated correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarker, particularly in preclinical AD. Additionally, the link between BIN1 loci and AD pathology was partially mediated by CSF sTREM2.